OBJECTIVE: Diabetic nephropathy represents the leading cause of end-stage kidney disease in developed countries. Cardiovascular outcome trials have found that in participants who received a glucagon-like peptide-1 receptor agonist (GLP1RA) and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), the risk of incidence and progression of diabetic nephropathy in type 2 diabetes mellitus was reduced. The aim of this study was to compare the decline in estimated glomerular filtration rate (eGFR) among people taking a GLP1RA with that among people taking an SGLT2i in a real-world setting.
METHODS: Data for 478 patients with type 2 diabetes mellitus who initiated therapy with a GLP1RA (n = 254) or an SGLT2i (n = 224) between January 1, 2018 and December 31, 2021 were extracted. The primary outcome was any reduction ≥30% in eGFR after the start of therapy. Weight loss and drug discontinuation were also assessed.
RESULTS: Over a median follow-up of 24 months, an eGFR reduction ≥30% occurred in 34 of 254 patients (13.4%) starting a GLP1RA and in 26 of 223 patients (11.6%) starting an SGLT2i (hazard ratio = 0.89; 95% CI, 0.54-1.49; P = 0.67). Median eGFR change over the whole follow-up was similar between groups (SGLT2i: median, -2 mL/min/1.73 m2; 25th, 75th percentile, -13, 8 mL/min/1.73 m2; GLP1RA: median, 0 mL/min/1.73 m2; 25th, 75th percentile, -10, 7 mL/min/1.73 m2; P = 0.54). No worsening of kidney function was observed, even when considering the ratio eGFR mean. The value of eGFR at baseline indicated a statistically significant indirect correlation with the observed absolute value of eGFR change over the follow-up (ρ = -0.36; P < 0.001). The difference in eGFR changes over time observed by eGFR categories was statistically significant (P = 0.0001) in both treatment groups. No significant differences in weight loss and drug discontinuations were observed between groups.
CONCLUSIONS: Although acting on different molecular mechanisms, both GLP1RA and SGLT2i might have similar effects on eGFR decline in diabetes, as suggested by the results of the present study conducted in a real-world setting. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

The efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RA) in type 2 diabetes mellitus is well-established. GLP1-RAs are not approved for use in type 1 diabetes mellitus (T1DM). A 34-year-old woman with a 23-year history of T1DM presented for review for weight gain (weight 63 kg, BMI 26.9 kg/m2) and increased HbA1c (8.3%) and glycemic variability. Subcutaneous semaglutide (1 mg weekly) was commenced. After two months, there was decrease in weight by 12 kg, body fat percent by 15%, visceral fat by 7%, and a reduction in insulin dose, glycemic variability, and HbA1c. Semaglutide could be an important adjunct to insulin treatment in T1DM.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is reported to have cardiac benefits, but its effects on preventing atrial fibrillation (AF) remain inconclusive. This study aimed to investigate whether semaglutide can prevent AF occurrence in patients with type 2 diabetes mellitus (T2DM), obesity, or overweight.
METHODS: We searched MEDLINE, EMBASE, the Cochrane CENTRAL database, and clinicaltrials.gov from inception to December 29, 2023. Randomized controlled trials of semaglutide in patients with T2DM, obesity, or overweight were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95 % confidence intervals (CIs) were calculated for the overall population and subgroups.
RESULTS: Twenty-one trials comprising 25957 patients were included. In the overall pooled analysis, semaglutide decreased AF occurrence compared to control drugs (RR 0.70, 95 % CI 0.52-0.95). This result was consistent in trials using other antihyperglycemic medications as controls (RR 0.43, 95 % CI 0.21-0.89), but not in placebo-controlled trials (RR 0.77, 95 % CI 0.56-1.07). The outcome was favorable for patients with T2DM (RR 0.71, 95 % CI 0.52-0.97), but not for patients with overweight or obesity (RR 0.56, 95 % CI 0.18-1.73). Results varied by type of semaglutide, with oral semaglutide showing an RR of 0.49 (95 % CI 0.25-0.97) and subcutaneous semaglutide showing an RR of 0.77 (95 % CI 0.55-1.07).
CONCLUSIONS: Semaglutide was associated with a reduced risk of AF occurrence in the overall analysis. Favorable outcomes were observed in subsets using other antihyperglycemic medications as controls, in patients with T2DM, and with oral semaglutide.

BACKGROUND: Glucagon-like peptide-1 receptor agonist (GLP-1A) medications are gaining widespread popularity for the treatment of obesity. The optimal use of these drugs in pediatric bariatric populations, and especially in those considering metabolic and bariatric surgery (MBS), is yet to be established. We sought to characterize current practice patterns of GLP-1A use at major pediatric bariatric centers across the United States.
METHODS: We administered an online survey to a purposive sample of 46 surgeons who perform MBS on children and adolescents. Survey questions explored practices prescribing GLP-1As in patients considering MBS, holding them prior to elective operations, and restarting them postoperatively following MBS. Responses were summarized with descriptive statistics and inductive content analysis.
RESULTS: There were 22 responses (48% response rate) representing 19 institutions. Most (86%) respondents do sometimes prescribe GLP-1As for patients considering MBS, but the specific indications vary. Practices for holding GLP-1As preoperatively also vary, from not at all to holding for 2 wk. Over half (55%) of respondents sometimes restart GLP-1As after MBS. Free-response themes included still-evolving preoperative utilization patterns, difficulty with access and insurance coverage, and a lack of data informing GLP-1A use in the pre and postoperative periods.
CONCLUSIONS: Given the increasing use of these medications for weight loss purposes, this substantial variation in practice highlights a need for further research to examine the safest and most effective use of GLP-1As in the pre and postoperative periods and for practice guidelines to standardize care pathways in pediatric bariatric contexts.

Currently, there is no known cure for diabetes. Different pharmaceutical therapies have been approved for the management of type 2 diabetes mellitus (T2DM), some are in clinical trials and they have been classified according to their route or mechanism of action. Insulin types, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sodium-glucose cotransporter type 2 inhibitors, and incretin-dependent therapies (glucagon-like peptide-1 receptor agonists: GLP-1R, and dipeptidyl peptidase 4 inhibitors: DPP-4). Although some of the currently available drugs are effective in the management of T2DM, the side effects resulting from prolonged use of these drugs remain a serious challenge. GLP-1R agonists are currently the preferred medications to include when oral metformin alone is insufficient to manage T2DM. Medicinal plants now play prominent roles in the management of various diseases globally because they are readily available and affordable as well as having limited and transient side effects. Recently, studies have reported the ability of phytochemicals to activate glucagon-like peptide-1 receptor (GLP-1R), acting as an agonist just like the GLP-1R agonist with beneficial effects in the management of T2DM. Consequently, we propose that careful exploration of phytochemicals for the development of novel therapeutic candidates as GLP-1R agonists will be a welcome breakthrough in the management of T2DM and the co-morbidities associated with T2DM.

Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.

BACKGROUND: Glucagon-like peptide-1 receptor agonist use has increased over the last decade for glycemic control in type 2 diabetes mellitus, cardiovascular risk reduction, and weight loss. Clinical trials indicate that gastrointestinal adverse effects are commonly experienced and severe hypoglycemia is rare; however, there is little data regarding glucagon-like peptide-1 receptor agonist in overdose.
METHODS: We performed a retrospective chart review evaluating and characterizing glucagon-like peptide-1 receptor agonist exposures reported to a single poison center between 2006 and 2023. Patient demographics, circumstances of exposure, clinical effects, and outcomes were abstracted from charts. Descriptive statistics were utilized to summarize demographic information and clinical factor data.
RESULTS: A total of 152 charts met inclusion criteria. Therapeutic errors accounted for 91% of exposures. Most patients (67%) reported no symptoms, although not all patients were followed to a definitive outcome. Nausea, vomiting, generalized weakness, and abdominal pain were the predominant symptoms reported. Most patients (62%) were monitored and closely followed in the home setting. Hypoglycemia was rare but occurred in the setting of a single agent glucagon-like peptide-1 receptor agonist exposure in two patients. Two additional patients who developed hypoglycemia involved co-administration of insulin. 21% of the exposures were related to errors on initial use of the pen.
CONCLUSIONS: Exposures to glucagon-like peptide-1 receptor agonist have increased substantially over the years. Effects from an exposure tended to be mild and primarily involve gastrointestinal symptoms. Hypoglycemia was rare. Therapeutic and administration errors were common. Education on pen administration may help to reduce errors.

Many individuals with type 1 diabetes (T1D) do not achieve their management goals. The patient perspective on unmet needs in T1D may guide the role of adjunctive therapies, including glucagon like peptide-1 receptor agonists (GLP-1RAs). A quantitative online survey (n = 133) assessed (1) self-reported demographic and management data, (2) management priorities, satisfaction, and willingness to use adjunctive therapies and (3) conducted a risk-benefit analysis using three masked drug profiles (1.8 mg vs 0.6 mg liraglutide vs placebo). A subgroup of respondents (n = 20) participated in semi-structured interviews to extend upon survey insights. Needs were unmet by current treatment in 28% of surveyed individuals. The greatest unmet needs included (1) glycemia, (2) management-related fatigue, and (3) weight management. Most respondents (94%) indicated that they would use adjunctive therapies. The preferred administration route was daily tablets (66%) followed by weekly injections (32%). Metabolic improvements were most valued (reduction in hypoglycemia, hyperglycemia). Most respondents (94%) preferred the liraglutide risk-benefit profile (1.8 mg, then 0.6 mg) over placebo. Individuals with T1D self-report many unmet needs. While not currently approved in T1D, GLP-1RA properties align with many management priorities reported by individuals with T1D.

Background: The expanding roles and popularity of glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has created access barriers to medication use. We sought to describe an adverse drug event which occurred after reinitiation of a GLP-1 receptor agonist following a prolonged lapse in therapy due to poor medication access. Case Summary: Once-weekly injectable semaglutide was prescribed to an outpatient 33-year-old male for chronic weight management. After a delayed initiation due to global shortage, semaglutide was initiated and titrated over five months before a seven week lapse in therapy due to prior authorization interruption. Despite the extended treatment gap, the patient was directed to reinitiate semaglutide at the target dose rather than starting dose, which was followed by recurrent, symptomatic nausea and vomiting requiring medical intervention. Practice Implications: A prolonged lapse in GLP-1 receptor agonist therapy, typically defined as missing three or more doses of a once-weekly injectable, warrants consideration of reinitiation at a reduced dose, personalized to the patient\'s prior gastrointestinal tolerability, efficacy goals, and therapy lapse duration. Therapy lapses with GLP-1 receptor agonists may be prevented by utilizing a multi-modal approach including extended dosing intervals, intermediate doses, agent interchange, efficient prior authorization communication, and cautious initiation of GLP-1 recent agonists while supply cannot meet demand.

Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin-eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.